PTH stimulates both bone resorption and formation. It may, therefore, be important in the pathogenesis and treatment of conditions in which bone mass is lost due to an imbalance between resorption and formation, such as osteoporosis and hyperparathyroidism. The overall goal of this project is to determine the mechanisms by which PTH stimulates resorption. Two of the primary findings were that PTH stimulates IL-6 mRNA, and that stimulation of osteoclast activity by PTH requires IL-6, which may act synergistically and redundantly with other autocrine cytokines. The current application looks further into these findings: Aim 1 will test the hypothesis that PTH-induced osteoclast differentiation depends on synergistic/redundant actions of IL-1, IL-6, IL-11 and/or LIF. Aim 2 will test the hypothesis that PTH-induced osteoclast differentiation depends on autocrine actions of IL-11 and/or LIF. Aim 3 will test whether PTH induced secretion of IL-6 protein depends on translational regulation rather than transcriptional regulation. Aim 4 will investigate whether the transient nature of PTH-induced IL-6 mRNA depends on PTH receptor desensitization due to betaARK-like kinases.